This invention relates to the preparation of a novel crystalline lactone and its use in prostaglandin synthesis.
The synthetic prostaglandin 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2xcex1 and its ester derivatives, in particular the isopropyl ester (2), are potent drugs for the treatment of glaucoma and ocular hypertension. Optimum therapeutic benefit is achieved when compound (2) is used in the form of the dextrorotatory single enantiomer (+)-2, as depicted below. For development as a pharmaceutical product, an economically viable route is required for the synthesis of (+)-2 in quantities of at least 1 kg. 
EP-A-0639563 describes biological studies of compound 2 and analogues, and synthetic methods which are applicable to its preparation. The synthetic strategy employed is based on that used by Corey in his pioneering synthesis of prostaglandin F2xcex1(Corey and Cheng, The Logic of Chemical Synthesis, Wiley, 1989, p. 250-266 and references therein), wherein the cyclopentane ring embedded in a lactone intermediate of type 3 (PG=protecting group, e.g. Me) has relative stereochemistry correctly defined across four chiral centres. Lactones of type 3 can be prepared in single enantiomer form. Although such a route was successfully utilised to prepare small quantities of (+)-2 for preliminary biological evaluation, for a number of reasons it is unsuitable for industrial manufacture as a high-purity pharmaceutical product for administration to human patients. At least 15 steps (from cyclopentadiene) are required, with loss of yield in individual steps exacerbated by the linear nature of the synthesis. Fractional column chromatography is required after many of these steps to effect purification of intermediates. For example, a late stage stereoselective reduction of a 15-keto function in the xcfx89-side chain using (xe2x88x92)-B-chlorodiisopinocampheylborane requires the removal of the unwanted 15S isomer, formed as a by-product, by a chromatographic separation. 
An alternative and more convergent approach to prostaglandins involves addition of a cuprate reagent, incorporating the entire xcfx89-side chain, to the tricyclo[3.2.0.02.7]heptanone 4 (Lee et al, J. Chem. Soc., Perkin Trans 1, 1978,1176). Tricyclic ketone 4 is prepared from a TBDMS-protected bromohydrin which is in turn derived from bicyclo[3.2.0]hept-2-en-6-one (5). In comparison to routes proceeding by a Corey lactone of type 3, significantly fewer steps are required. For example, preparation of prostaglandin F2xcex1 from compound 5 requires only 8 steps (10 steps from cyclopentadiene). Avoidance of awkward late-stage reduction to establish the required configuration of the C-15-OH functionality provides another advantage.
EP-A-0074856 describes resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (5) by forming diastereomeric salts of its xcex1-hydroxysulfonic acid derivative with a chiral amine, and separation by crystallisation.
Certain lactones are described in Newton et al, Tetrahedron, 1980, 2163. None is crystalline.
This invention is based on the unexpected discovery of a crystalline lactone 1 
This compound can be used in the stereoselective synthesis of 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2xcex1 and its ester derivatives, for example (+)-2. The crystalline lactone can be obtained in highly pure form. The crystallinity of the lactone is crucial in enabling impurities to be removed at this stage without resort to column chromatography. This provides the basis for an industrially viable synthesis of the prostaglandin 2 for pharmaceutical use.
According to the invention, this discovery may also be applied to other substituted 16-phenoxy prostaglandins, where the substituent is haloalkyl, alkyl or halide. The alkyl group may have up to 6 C atoms. Halide is preferably 3-Cl.
By way of illustration, the synthesis of the lactone 1 is depicted in Scheme I. All reactants depicted are used in enantiomerically enriched form, typically in  greater than 95% ee or higher.
Step (i) is the preparation of the tricyclic ketone 4. This is achieved by treatment of the bromohydrin 6 with base in an appropriate solvent, preferably potassium tert-butoxide in toluene. The unstable tricycle 4 is used without purification in step (iii). It is not necessary to evaporate the tricycle solution to dryness.
Step (ii) is the formation of an alkenylcuprate reagent from the vinyl iodide 7, precursor to the xcfx89-side chain. The preparation of vinyl iokide 7 in enantiomerically enriched form is disclosed in U.S. Pat. No. 6,214,611, issued Apr. 10, 2001, entitled Process for the Preparation of Prostaglandin precursors, and claiming priority from British Patent Application No. 9908327.1. The vinyl iodide is metallated with an alkyllithium reagent, preferably tert-butyllithium, and then treated with a cuprate of the form RCu(CN)Li where R is a non-transferable group which may be 2-thienyl. Step (iii) is reaction of the alkenylcuprate with the tricycle to form the bicyclic ketone 8.
Step (iv) is the Baeyer-Villiger reaction producing the lactone 1. A peracid, preferably peracetic acid, is used, resulting in a 3:1 mixture of regioisomers, isolated as an oil. Further processing is then required to render this material as usable in subsequent steps. Conveniently, the minor and unwanted regioisomer can be selectively hydrolysed by treatment with aqueous alkali, for example, aqueous sodium hydroxide in acetonitrile. Extraction of the unreacted lactone 1 into an organic solvent, followed by evaporation of solvent, yields a solid residue which can be recrystallised at low temperature to give highly pure crystalline material with convenient handling and storage characteristics. These processing operations are pivotal to the success of the overall synthetic route. 
Scheme II summarises the conversion of lactone 1 to the target prostaglandin (+)-2, using conventional processes (for analogous methods see Lee et al, J. Chem. Soc., Perkin Trans 1, 1978,1176; and EP-A-0639563). Typically, reduction to the lactol using diisobutylaluminium hydride is followed by Wittig reaction with the ylide generated from (4-carboxybutyl)triphenylphosphonium bromide and potassium tert-butoxide. Esterification and O-deprotection steps complete the synthesis. 